Stroke is the third leading cause of death and the leading cause of adult disability in the United States. Each year in the US, 750,000 Americans suffer a symptomatic stroke, and over 11 million suffer an asymptomatic stroke. The central aim of this proposal is to demonstrate that paramedic initiation of the neuroprotective agent magnesium sulfate in the field is an efficacious and safe treatment for acute stroke. The proposal is a multicenter, randomized, double-blind, phase 3 clinical trial, using intention to treat analysis, of magnesium sulfate versus placebo among ambulance-transported patients with acute stroke. Study agent will be initiated within two hours of stroke onset in all enrolled individuals, and within one hour of onset in approximately one-half of enrolled individuals. A total of 1298 patients will be enrolled, 649 in each treatment arm. The dose of magnesium sulfate employed will be 4 gram IV loading dose over 15 minutes followed by 16 gram IV maintenance dose over 24 hours. The primary study hypothesis is that treatment with magnesium sulfate improves the long-term functional outcome of hyper-acute stroke patients. The primary study endpoint will be the difference in distribution of scores between magnesium sulfate and placebo groups on the modified Rankin Scale measure of global handicap, assessed 3 months poststroke. Secondary analyses will analyze treatment efficacy on endpoints indexing neurologic deficit, activities of daily living, global outcome, and quality of life, and in pre-specified patient subgroups, including patients with ischemic stroke, ischemic stroke co-treated with tissue plasminogen activator, ischemic stroke not co-treated with tissue plasminogen activator, intracerebral hemorrhage, patients treated within 15-60 minutes of symptom onset, and within 61-120 minutes of symptom onset. Successful conduct of the trial will serve as a pivotal test of the promising neuroprotective agent magnesium sulfate in acute stroke, and will also demonstrate for the first time that field enrollment and treatment of acute stroke patients is a practical and feasible strategy for phase 3 stroke trials, permitting enrollment of greater numbers of patients in hyper-acute time windows. [unreadable]